Ben Z. Stanger, MD, PhD

ACGT – Edward Netter Memorial Investigator Award in Cell and Gene Therapy Research for Pancreatic Cancer

Cell-based therapies for cancer have been highly successful in blood cancers such as leukemia and lymphoma. These therapies take the form of chimeric antigen receptor T cells (CAR T cells), which recognize and kill cancer cells. However, translating these therapeutic successes to cancers of internal organs – tumors of the lung, breast, colon, etc. – has been challenging. A major reason for this difficulty is that these “solid tumors” are protected by layers of protein and cells that shield the cancer from immune attack. This barrier to anti-tumor immunity is called the tumor microenvironment (TME), and pancreatic cancer represents the most extreme case of this impermeability. Our proposal seeks to disrupt this obstacle so that CAR T cells may gain entry to the tumor and exert their anti-cancer activity.

Our strategy contains two approaches. The first involves KRAS – a cancer-causing mutant protein that is the source of over 90% of pancreatic cancers. Recent advances in drug development have resulted in several chemical inhibitors of KRAS with dramatic anti-cancer effects in animal models and patients (leading already to FDA approvals in certain cancers). KRAS inhibitors exert most of their activity by killing cancer cells. However, a fortuitous side benefit is that these drugs also reshape the TME to allow immune cells (especially T cells) to infiltrate tumors. Our preliminary data in mice demonstrate that treatment with a KRAS inhibitor allows more T cells (including CAR T cells) to enter the tumor, resulting in greater anti-cancer activity. Our second approach involves the use of CAR T cells directed against a component of the tumor barrier – fibroblast activation protein (FAP). We have shown that CAR T targeting FAP can force their way into tumors, bringing other T cells (including other CAR T cells) along with them. As a result, combinations of anti-FAP CAR T cells with either chemotherapy or cancer-targeted CAR T leads to greater anti-tumor effects.

Our proposal includes studies in both animals and patients. Aim 1 extends our work on KRAS inhibitors and FAP CAR T cells in mouse models to understand how these interventions reshape the TME. We will also determine whether combining the two therapies can have additive effects, leading to cures (as suggested by our preliminary studies). Aims 2 and 3 focus on patients. Aim 2 builds on an ongoing clinical trial in pancreatic cancer of CAR T cells against mesothelin. Our goal is to determine whether pretreatment with a KRAS inhibitor before CAR T infusion results in a greater number of CAR T cells inside the tumor. Aim 3 involves a clinical trial of FAP CAR T cells scheduled for 2025 in which we will assess whether these CAR T cells penetrate patient tumors (as they do in our animal models) and reshape the TME in a favorable manner.

Collectively, these studies aim to break down the physical and immunological barriers limiting the efficacy of CAR T cell therapy for pancreatic cancer.

“We get a two-for-one benefit. We attack the cancer cell when we treat it with the KRAS inhibitor, but we also open up the opportunity for T cells to get into the tumor and do what we want them to do.”